Interstitial pneumonia is a refractory disease characterized by inflammation in the interstitial tissue of the lung (parts other than the pulmonary alveoli). It is known that in 50% of the patients with interstitial pneumonia, the disease'switches over to idiopathic pulmonary fibrosis and progresses in severity. Pulmonary fibrosis is a disease in which the lung becomes stiff and then shrinks, thereby the gas exchange becomes insufficient. When these symptoms progress, the patient finally suffers from respiratory distress, which leads to death. It is reported that there are 15,000 idiopathic pulmonary fibrosis patients in Japan, while there are 50,000 patients in the United States.
Currently, in regard to this disease, there has been a strong demand from patients and physicians for an effective drug or therapy, and pharmaceutical companies have paid attention thereto and put efforts into research and development. Nevertheless, there has been no effective medicament or therapeutic method established heretofore, and the survival time lasts 2 to 3 years.
Stanniocalcin 1 (STC1) is a dimeric glycoprotein hormone which was discovered in the gills of fishes and is also found in mammals. In addition to its role in the metabolism of phosphorus and calcium, STC1 is known to have various physiological activities, such as promotion of oxidative phosphorylation in mitochondria, a neuron and cardiac muscle protecting action, and a bone metabolism promoting action.
Specifically, the following findings have been reported. STC1 decreases the membrane potential of mitochondria in the cells through induction of uncoupling protein 2 (UCP2) (Non-Patent Documents 1 to 3). This decrease in the mitochondrial membrane potential via UCP2 leads to a decrease in intracellular peroxides (ROS), and brings about a decrease in the glucose dependency of mitochondria and an increase in lipid metabolism by mitochondria (Non-Patent Documents 1 to 3). Furthermore, STC1 induces uncoupling metabolism (resulting in an increase in the amount of lactic acid, an increase in the amount of oxygen consumption, and an increase in the amount of lipid metabolism), which is neither anaerobic metabolism nor aerobic metabolism. Uncoupling metabolism enables consumption of more energy and reduces peroxidation stress under the condition of starvation (or a disturbed environment), and therefore, it is believed that uncoupling metabolism is advantageous in the survival in a disturbed environment (Non-Patent Documents 3 and 4).
Non-Patent Document 5 and Patent Document 1 disclose that in a nephritis model mouse produced by administering a substance inducing nephritis (Anti-GBM Ab), fibrosis occurs in the kidney tissue of the mouse. It is also described that when a nephritis-inducing substance was administered respectively to a wild type (WT) mouse and a STC1-overexpressing mouse, it was demonstrated that the extent of fibrillization of the kidney tissue had been reduced in the kidney of the STC1-overexpressing mouse than in that of the WT mouse.
However, in this experiment using a model mouse, fibrillization occurred as a result of the inflammation of nephritis, and the inflamed tissue of the kidney was fibrillized. In these documents, there is no description indicating that STC1 has an anti-fibrotic action (fibroblast proliferation inhibiting action or the like). Furthermore, there is no description on pulmonary fibrosis.
In regard to STC1, utilization thereof has been proposed as pharmaceutical compositions based on the various physiological activities such as the adipocyte differentiation or maturation inhibitory activity, the promoting action of bone formation and the neuron protective action (Patent Documents 2 to 5). However, no relevant prior art that suggests the potential as a medicine for pulmonary fibrosis has been found.